PROJECT SUMMARY: Lymphoma is the sixth most common form of cancer in the United States, affecting an estimated 23 per 100,000 people. While there have been significant advances in our understanding of lymphoma biology and our ability to provide curative therapy, many patients with lymphoma continue to suffer poor outcomes with approximately 20,000 people dying from lymphoma in the US each year. Novel approaches to the diagnosis and treatment of lymphoma are urgently needed. This application is focused on elucidating the molecular mechanisms that regulate MALT1, a central oncoprotein in B-cell lymphoma. MALT1 is a cytoplasmic protein that serves to mediate antigen receptor- dependent lymphocyte activation, proliferation and survival, via stimulation of the canonical pro-survival NF-?B transcription factor. In B-lymphocytes, the antigen receptor is known as the B-cell receptor (BCR). In these cells, BCR-induced, MALT1-dependent NF-?B activation is a required event during the normal adaptive immune response, but dysregulated activation of this pathway can lead to lymphoma. Indeed, genetic analysis has revealed that in specific subtypes of B-cell lymphoma, malignant B cells highjack BCR signaling pathways in order to promote their own growth and survival. BCR stimulation results in assembly of the CARMA1-Bcl10-MALT1 (CBM) protein signaling complex, where MALT1 serves as the effector by carrying out two important functions. First, MALT1 acts as a scaffold to recruit and activate downstream signaling proteins, and second, MALT1 acts as a protease to cleave specific substrate signaling proteins and alter their activities. The critical importance of achieving appropriate regulation of MALT1 activity is demonstrated by the fact that gain-of-function mutations in BCR subunits or in CARMA1, resulting in exaggerated MALT1 activity, are recurrently detected in human B-cell lymphoma. Thus, MALT1 is the subject of intense investigation as a key regulator of B-lymphomagenesis and a promising new target for pharmaceutical inhibition. This proposal investigates the innovative hypothesis that specific proteins are capable of controlling MALT1 function, such that their loss in some subtypes of B-cell lymphoma may contribute to aberrant MALT1 activity. The presence of gain-of-function BCR or CARMA1 mutants may synergize with loss of such proteins in promoting lymphomagenesis; conversely, loss alone may be pathogenic. Our goals for this proposal are to elucidate the molecular underpinnings by which specific protein-protein interactions can abrogate MALT1 activity, to determine how this interaction influences lymphocyte growth and survival, and to utilize this information to inform the design of novel therapeutic approaches to MALT1-dependent lymphoma.